tbuckley/cabot-search huggingface dataset:
Abstract A009: ZMYND8 is an epigenetic regulator of 27-hydroxycholesterol that promotes tumorigenicity of breast cancer stem cells
Authors: Weibo Luo, Maowu Luo
Journal: Cancer Research (2022)

Abstract 27-hydroxycholesterol (27-HC) is the most abundant oxysterol that increases the risk of breast cancer progression. However, little is known about epigenetic regulation of 27-HC metabolism and its role in breast tumor initiation. Using genetic mouse mammary tumor and human breast cancer models, we showed here that the histone reader ZMYND8 was selectively expressed in breast cancer stem cells (BCSCs) and promoted epithelial-mesenchymal transition (EMT), BCSC maintenance and self-renewal, and oncogenic transformation through its epigenetic functions, leading to breast tumor initiation. Mechanistically, ZMYND8 was a master transcriptional regulator of 27-HC metabolism. It increased cholesterol biosynthesis and oxidation but blocked cholesterol efflux and 27-HC catabolism leading to accumulation of 27-HC in BCSCs. Consequently, 27-HC promoted EMT, oncogenic transformation, and tumor initiation through activation of liver X receptor. These findings reveal that ZMYND8 is an epigenetic booster that drives breast tumor initiation through metabolic reprogramming. Citation Format: Weibo Luo, Maowu Luo. ZMYND8 is an epigenetic regulator of 27-hydroxycholesterol that promotes tumorigenicity of breast cancer stem cells. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A009.
Abstract A023: Sensitivity/resistance mechanisms to KDM5 inhibition in basal breast cancer
Authors: Benedetto DiCiaccio, Evangelia Papachristou, Malvina Papanastasiou, Andrew Reiter, Jason Carroll, Kornelia Polyak
Journal: Cancer Research (2022)

Abstract We previously described that the KDM5B histone H3 lysine 4 demethylase is amplified and overexpressed in luminal estrogen receptor positive breast cancer, and its activity is associated with resistance to endocrine therapies. We have found that the KDM5A paralog is specifically amplified and overexpressed in basal breast cancer, providing a novel therapeutic opportunity for an aggressive breast cancer subtype. To identify modulators of KDM5 inhibitor sensitivity in KDM5A-amplified basal breast cancer, we performed a genome wide CRISPR viability screen in a KDM5A-amplified basal breast cancer cell line. Our CRISPR screen results and follow up studies implicate Rho-GTPase signaling and the transcriptional repressor ZBTB7A as modulators of cellular response to KDM5 inhibition. We are currently investigating the underlying mechanisms for how these components alter sensitivity/resistance to KDM5 inhibition. Our results suggest potential therapeutic opportunities of inhibiting the KDM5 family of H3K4 demethylases in basal breast cancer. Citation Format: Benedetto DiCiaccio, Evangelia Papachristou, Malvina Papanastasiou, Andrew Reiter, Jason Carroll, Kornelia Polyak. Sensitivity/resistance mechanisms to KDM5 inhibition in basal breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A023.
Abstract B012: Defining the role of the BAF complex in primary liver cancers
Authors: Margarita M. Dzama, Deena M. Scoville, Emma D. Bucklan, Jesse R. Raab
Journal: Cancer Research (2022)

Abstract Incidence and mortality from primary liver cancer are increasing and few effective therapies exist for this deadly disease. Mutations in genes important for chromatin mediated gene regulation commonly occur in both hepatocellular carcinoma and cholangiocarcinoma, the two most common primary liver cancers. Chromatin regulators have been shown to be key modulators of both sensitivity and resistance to therapy response, and therapeutic targeting of chromatin regulators is under development for a wide range of cancers. To uncover chromatin genes that modulate therapy response, we performed epigenome-focused CRISPR screening in the presence of multiple kinases inhibitors (sorafenib, donafenib, cabozantinib). We found that disruption of a specific form of the SWI/SNF chromatin remodeling complex, called BAF, led to therapy resistance. The BAF complex is frequently mutated in both hepatocellular carcinoma and cholangiocarcinoma. Recent studies show that loss of ARID1A and ARID1B, members of the BAF complex, gives rise to liver tumors with morphologies of both hepatocellular carcinoma and cholangiocarcinoma. Critically, because multikinase inhibitors are the most common treatments for advanced hepatocellular carcinoma, our findings suggest patients with BAF mutations would not respond well to these drugs. Using gene expression analysis, genome-wide chromatin localization, and chromatin accessibility assays we are uncovering how altered chromatin state underlies multikinase inhibitor response in BAF mutant tumors. Using high-throughput epigenome focused CRISPR screens we will identify novel modulators of therapy response in liver cancer. Citation Format: Margarita M. Dzama, Deena M. Scoville, Emma D. Bucklan, Jesse R. Raab. Defining the role of the BAF complex in primary liver cancers. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B012.
Abstract B001: Chromatin engineering using a dCas9-based inducible dimerization system
Authors: Mary Bergwell, JinYoung Park, Laura Pistoni, Jacob G. Kirkland
Journal: Cancer Research (2022)

Abstract Epigenetic cancers lead to tumor progression via oncogene activation, tumor suppressor silencing, cell fate transitions, and genomic instability. Approximately 50% of tumors have alterations in Chromatin regulators. One group of Chromatin regulators, the mSWI/SNF complexes, are mutated in 20% of tumors making them one of the most mutated chromatin regulator complexes in cancer. In the past, the mechanism of action of ATP-dependent chromatin regulators, such as mSWI/SNF was largely explored using in vitro methods based on measurements of nucleosome mobility. These studies were limited by the fact that these assays were not sensitive to tissue-specific chromatin modifications, topology, long-range interactions, and complex patterns of histone modifications as well as patterns of DNA methylation and human disease mutational backgrounds. To circumvent these problems, we developed the FIRE-Cas9 system that allows one to recruit a specific chromatin regulator and follow the consequences with minute-by-minute kinetics on physiologic chromatin. I can examine any locus of biological or medical importance in virtually any cell type using this technique. We can recruit endogenous proteins or protein complexes such as different mSWI/SNF complexes, histone methyltransferases, or histone demethylases and assay changes in chromatin state and transcriptional state. Because chromatin regulator complexes have alterations in many human cancers, it is imperative to understand the mechanism of action of these complexes with unparalleled precision as a basis for therapeutic development. The FIRE-Cas9 system allows one to do this for the first time. Citation Format: Mary Bergwell, JinYoung Park, Laura Pistoni, Jacob G. Kirkland. Chromatin engineering using a dCas9-based inducible dimerization system. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B001.
Abstract IA019: Ectopic levels of low-complexity domain interactions repress endogenous oncogenic transcription
Authors: Shasha Chong
Journal: Cancer Research (2022)

Abstract Mammalian transcription factors (TFs) ubiquitously contain intrinsically disordered low-complexity domains (LCDs) that perform transactivation functions. Recent studies have shown that dynamic, multivalent, and selective interactions between TF LCDs play an essential role in transactivation, but how such interactions mediate gene transcription remains unclear. It has been proposed that liquid-liquid phase separation (LLPS) of TFs driven by extensive LCD-LCD interactions is the mechanism underlying transactivation. Here, we investigate how tuning the level and localization of LCD-LCD interactions in vivo affects transcription of endogenous human genes. By quantitative single-cell imaging, we reveal that efficient gene activation by the oncogenic TF EWS/FLI1 requires narrow optimum of LCD-LCD interactions at its target genes associated with GGAA microsatellites. Increasing LCD-LCD interactions toward putative LLPS represses transcription of these genes in Ewing sarcoma cells. Likewise, ectopically creating LCD-LCD interactions to sequester EWS/FLI1 into a well-documented LLPS compartment, the nucleolus, represses EWS/FLI1 -driven transcription and inhibits malignant transformation of Ewing sarcoma. In addition, using live-cell single-molecule imaging, we show that a TF diffuses significantly more slowly in the nucleolus than in the nucleoplasm, demonstrating an important impact of LLPS on TF dynamic behaviors and single-molecule diffusion measurement as an effective approach to diagnose LLPS in vivo. Our findings show how altering the balance of LCD-LCD interactions can influence transcriptional regulation and suggest a potential therapeutic strategy for targeting disease-causing TFs. Citation Format: Shasha Chong. Ectopic levels of low-complexity domain interactions repress endogenous oncogenic transcription. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA019.
Abstract IA020: Therapeutic targeting of MLL complexes in cancer
Authors: Scott A. Armstrong
Journal: Cancer Research (2022)

Abstract Inappropriate expression of genes such as the homeotic (HOX) genes is found in up to 40% of cases of Acute Myelogenous Leukemia (AML). Two well-defined genetic subsets, those with MLL-rearrangements and those with NPM1 mutations, are known to possess high-level expression of HOX and MEIS1 genes and have been shown to be dependent on continued expression of these genes. Recent studies have defined the chromatin-bound protein complexes that maintain this aberrant gene expression. Furthermore, multiple groups including ours have now developed small molecule inhibitors of chromatin-associated complexes. Some of these small molecules, including those targeting DOT1L, EZH2, and Bromodomains are at various stages of clinical development. Another approach to target chromatin associated complexes is via disruption of protein-protein interactions. One such protein-protein interaction that is being targeted is the interaction between the histone methyltransferase MLL1 and Menin, an approach that has also been shown to reverse leukemogenic HOX/MEIS1 gene expression. We have developed novel, potent and orally bioavailable MLL1-Menin inhibitors and have brought one of these small molecules to clinical assessment. Inhibition of the MLL1-Menin interaction in MLL-rearranged and NPM1 mutant AML cells leads to loss of Menin from chromatin, destabilization of the Menin protein and specific changes in chromatin state that include loss of the MLL1 complex at select loci. This results in selective reversal of leukemogenic gene expression, changes in occupancy of multiple other chromatin complexes, rapid cellular differentiation and cell death. Also, we have recently found this interaction to be critical in subtypes of Sarcoma opening up novel potential therapeutic opportunities. These molecules have remarkable preclinical activity in human disease models including patient derived xenograft (PDX) models, show minimal toxicity and are now in phase I/II clinical trials. Inhibition of protein-protein interactions represents a potentially effective approach to destabilize chromatin associated complexes for cancer therapy. Citation Format: Scott A. Armstrong. Therapeutic targeting of MLL complexes in cancer. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA020.
Abstract IA007: Transforming chromatin: Oncohistone mutations in pediatric high-grade glioma
Authors: Kaitlin Budd, Chang-Hyuk Kwon, Lawryn H. Kasper, Christopher Roberts, Jordan Roach, Jennifer Ocasio-Adorno, Jon D. Larson, Suzanne J. Baker
Journal: Cancer Research (2022)

Abstract Pediatric diffuse high-grade gliomas (HGGs) are a heterogeneous spectrum of disease with abysmal survival rates. Approximately half of diffuse high-grade gliomas in children arise in midline structures predominantly the brainstem, but also thalamus, cerebellum and spinal cord. Approximately 80% of these tumors harbor H3 K27M mutations, which result in dramatic depletion of the post-translational modification H3K27me3. Alternative mutations in diffuse midline gliomas can result in similar reduction of H3K27me3, leading to a redefined classification of this collection of tumors as diffuse midline glioma, H3 K27-altered. In contrast, distinct histone H3 mutations, H3.3 G34R/V, are found in approximately 30% of diffuse gliomas arising in the cerebral hemispheres of older adolescents and young adults, defining the tumor subgroup of diffuse hemispheric glioma, H3 G34-mutant. The striking spatiotemporal pattern of these histone mutations, termed oncohistones, indicates an intimate association between epigenetic dysregulation, brain development, and tumorigenesis. We will discuss use of genetically engineered and patient-derived models to investigate the contribution of oncohistone mutations to disrupted development, epigenetic dysregulation and gliomagenesis. Citation Format: Kaitlin Budd, Chang-Hyuk Kwon, Lawryn H. Kasper, Christopher Roberts, Jordan Roach, Jennifer Ocasio-Adorno, Jon D. Larson, Suzanne J. Baker. Transforming chromatin: Oncohistone mutations in pediatric high-grade glioma. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA007.
Abstract B031: PRC2 inhibitor suppresses angiogenesis in Hepatocellular carcinoma (HCC) by up-regulation of anti-angiogenic factors vasohibin1 (VASH1) and tissue inhibitor of metalloproteinases 3 (TIMP-3)
Authors: Hailong Zhang
Journal: Cancer Research (2022)

Abstract Tumor-associated angiogenesis plays a crucial role in the progression of tumor, especially in highly vascularized cancer, such as Liver hepatocellular carcinoma (LIHC), ovarian cancer, lung cancer, human head and neck cancers. Clinical research has shown that LIHC cells upregulate expression of vascular endothelial growth factor A (VEGFA), and induce proliferation and migration of epithelial cells under hypoxia condition, however, the mechanism of angiogenesis has not been completely elucidated in LIHC, especially in epigenetic regulation level. Polycomb repressive complex 2 (PRC2) is a multi-subunit protein complex that catalyzes the methylation of histone H3 at lysine 27, Enhancer of Zeste homolog 2 (EZH2) is the catalytic subunit, while embryonic ectoderm development (EED) recognizes H3K27me3 and enhance the catalytic activity of EZH2. A recent study suggests PRC2 promote angiogenesis in human ovarian carcinoma, while the detailed mechanism this process has not been illustrated. In this paper, we show BR1763, a potent, selective and orally bioavailable small-molecule inhibitor of EED, inhibits PRC2 activity, promote expression of vasohibin1 (VASH1) and tissue inhibitor of metalloproteinases 3 (TIMP3) in certain Hepatocellular Carcinoma (HCC) cells, and induces tumor growth inhibition by suppression of tumor-associated angiogenesis in vivo. Citation Format: Hailong Zhang. PRC2 inhibitor suppresses angiogenesis in Hepatocellular carcinoma (HCC) by up-regulation of anti-angiogenic factors vasohibin1 (VASH1) and tissue inhibitor of metalloproteinases 3 (TIMP-3). [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B031.
Abstract IA002: Structural basis of chromatin transcription
Authors: Lucas Farnung
Journal: Cancer Research (2022)

Abstract In eukaryotes, RNA polymerase (Pol) II transcribes chromatin and must move past nucleosomes, often resulting in nucleosome displacement. How Pol II unwraps the DNA from nucleosomes to allow transcription and how DNA rewraps to retain nucleosomes has been unclear. I will present the 3.0 Å cryo–electron microscopy structure of a mammalian Pol II-DSIF-SPT6-PAF1c-TFIIS-nucleosome complex stalled 54 base pairs within the nucleosome. The structure provides a mechanistic basis for nucleosome retention during transcription elongation where upstream DNA emerging from the Pol II cleft has rewrapped the proximal side of the nucleosome. The structure uncovers a direct role for Pol II and transcription elongation factors in nucleosome retention and explains how nucleosomes are retained to prevent the disruption of chromatin structure across actively transcribed genes. Importantly, the structure also provides the mechanistic basis for the survival of histone marks during transcription. Citation Format: Lucas Farnung. Structural basis of chromatin transcription. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA002.
Abstract B028: CDK12/13 inhibition antagonizes resistance to KRASG12C inhibitors
Authors: Yaakov E. Stern, Pompom Ghosh, Hannah L. Walker-Mimms, John W. Mosior, Denis Imbody, Hitendra S. Solanki, Andrii Monastyrskyi, Derek R. Duckett, Eric B. Haura
Journal: Cancer Research (2022)

Abstract Covalent inhibitors selectively targeting the KRASG12C mutation offer a promising new therapeutic opportunity for non-small cell lung cancer (NSCLC) patients, with partial or complete response observed in up to 40% of cancers harboring this lesion. As observed for other precision medicines targeting oncogenic drivers, resistance to these agents develops upon prolonged treatment. We have developed cell-based models of acquired resistance to the KRASG12C inhibitor sotorasib by serial passage of sotorasib-sensitive NSCLC cell lines in the presence of the drug. We have observed dynamic phosphorylation of the transcriptional elongation kinases CDK12 and CDK13 as well as hyperphosphorylation of a network of DNA damage response (DDR) proteins in sotorasib-resistant cell lines by phosphoproteomic profiling of resistant and sensitive cells. This is accompanied by elevated sensitivity to DDR pathway and CDK12/13 (e.g., SR-4835) inhibitors. Combined treatment of NSCLC cell lines with sotorasib and SR-4835 delays or prevents adaptation to sotorasib and the development of acquired resistance. Furthermore, gene expression profiling of SR-4835-treated cells reveals that CDK12/13 inhibition suppresses both DDR gene expression and metabolic pathways associated with resistance to sotorasib. This reflects synergy between SR-4835 and inhibitors targeting the DDR pathway in breast cancer cell lines and demonstrates that transcriptional elongation is a critical vulnerability for cells undergoing adaptation to KRASG12C inhibitors via DDR-dependent mechanisms. Citation Format: Yaakov E. Stern, Pompom Ghosh, Hannah L. Walker-Mimms, John W. Mosior, Denis Imbody, Hitendra S. Solanki, Andrii Monastyrskyi, Derek R. Duckett, Eric B. Haura. CDK12/13 inhibition antagonizes resistance to KRASG12C inhibitors. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B028.
Abstract B003: Inactivation mutations of Kmt2c/d license a molecular “field effect” and prime the urothelium for tumorigenesis
Authors: Naitao Wang, Mohini R. Pachai, Dan Li, Cindy Lee, Sarah Warda, Guojia Xie, Cheng Qian, Wai Pung E. Wong, Juan Yan, Wenhuo Hu, Alison Smith, Kai Ge, Sarat Chandarlapaty, Gopakumar V. Iyer, Jonathan E. Rosenberg, David B. Solit, Hikmat A. AI-Ahmadie, Ping Chi, Yu Chen
Journal: Cancer Research (2022)

Abstract Urothelial carcinoma (UC) is widely recognized to arise from a “field” of precancerous but histologically normal urothelium (HNU). The molecular mechanism that licenses the “field effect” remains elusive. Recent studies revealed prevalent KMT2C and KMT2D loss-of-function (LOF) mutations in HNU and cancer adjacent urothelium, suggesting their potential involvement in UC initiation. Here, we demonstrated that knockout (KO) of Kmt2c and/or Kmt2d in murine urothelial cells induced drastic alterations of cellular states by single cell RNA analysis, but was insufficient to induce robust histological changes. Kmt2c/d loss enhanced organoid formation efficiency, induced epithelial-mesenchymal transition (EMT), and impaired urothelial differentiation, indicating the augmented lineage plasticity after Kmt2c/d KO. Additionally, we identified that Kmt2c/d KO induced a pre-tumorigenic transcriptome with increased enrichments of gene sets associated with inflammation and decreased enrichments of gene sets associated with differentiation. Consequently, loss of Kmt2c/d sensitized urothelial cells to common oncogenic mutations to initiate UC in mouse models. We further observed that KO of Kmt2c/d increased tumorigenic susceptibility in carcinogen-induced UC model. Mechanistically, we observed decreased H3K4me1, H3K27Ac histone marks and decreased enhancer RNA production at the majority of enhancers that correlate with downregulation of urothelial specific lineage gene expression after Kmt2c/d KO. Furthermore, we observed increased Menin deposition on promoters of up-regulated genes. Blockade of Menin-KMT2A complex by small molecule inhibitor partially rescued the EMT and basal differentiation induced by Kmt2c/d KO. Together, our data posit that Kmt2c/d represents a key molecular determinant and their functional loss licenses a molecular “field effect” which primes the urothelium for oncogenic transformation. Citation Format: Naitao Wang, Mohini R. Pachai, Dan Li, Cindy Lee, Sarah Warda, Guojia Xie, Cheng Qian, Wai Pung E. Wong, Juan Yan, Wenhuo Hu, Alison Smith, Kai Ge, Sarat Chandarlapaty, Gopakumar V. Iyer, Jonathan E. Rosenberg, David B. Solit, Hikmat A. AI-Ahmadie, Ping Chi, Yu Chen. Inactivation mutations of Kmt2c/d license a molecular “field effect” and prime the urothelium for tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B003.